This invention relates to combinations of di-nitrogen heterocycles and their uses, inter alia in pharmaceuticals.
From the discovery of penicillin by Fleming in 1940""s there has been a constant search for new antibiotics, which search continues to this day. Although many antibiotics have been discovered, there is an on-going need for the discovery of new antibiotic compounds because of the emergence of drug resistant strains of bacteria. Thus, research on bacterial infection is a perpetual cycle of development of new antibiotics. When penicillin was first discovered, its broad-spectrum antibiotic activity was hailed as the xe2x80x9cmagic bulletxe2x80x9d in fighting many bacterial infections. However, over the years, many strains of bacteria have developed a resistance to penicillin and other currently available antibiotic drugs. No antibiotic drug is effective against all bacterial infections. Many antibiotic drugs available today have narrow-spectrum of activity, that is, they are effective against only few specific types of bacterial infections. Thus, for example, the majority of current antibiotic drugs are ineffective against syphilis and tuberculosis. In addition, some strains of syphilis, tuberculosis and other bacteria have developed resistance to currently available antibiotic drugs, which were effective drugs in the past.
Most bacteria which are resistant to a given drug also exhibit similar resistance to chemically similar drugs. Currently, many antibiotics are based on the xcex2-lactam chemical core structure of penicillin. Although other chemically diverse antibiotics, such as vancomycin, are currently available, it is only a matter of time before the emergence of bacterial strains which will be resistant to all currently available antibiotic drugs. Thus, to prevent a future world-wide epidemic of drug resistant bacterial infections, there is a never ending need for a development of antibiotic drugs with novel chemical structures. This invention addresses this goal among others.
It is, accordingly, an object of this invention to provide novel di-nitrogen heterocycle compounds and combinations of such compounds for use in the preparation of antibiotics and other pharmaceuticals.
A further object of the invention is to provide combinations of such compounds in a form such that resulting compositions have structurally and chemically diverse properties for use as research reagents and otherwise.
Yet another object is to provide products produced by processes herein disclosed for the preparation of pharmaceuticals and other useful chemical species.
A further object is to provide methods for the identification of useful drugs and reagents.
These and other objects will become apparent to persons of ordinary skill in the art from a review of the present specification and appended claims.
In one aspect, the present invention is directed to compounds having a di-nitrogen-containing heterocyclic portion to which pluralities of substituents are appended. In accordance with preferred embodiments, compositions are prepared comprising a plurality of such compounds, preferably more than three and even more preferably, more than six, such that such compositions can be seen to be mixtures of species having a di-nitrogen heterocyclic framework. It is preferred that the substituents appended to the framework, preferably the di-nitrogen heterocyclic frameworks as discussed hereinafter, be varied in terms of size, hydrophobicity, charge, chemistry, orientation, and subsequent reactivity. The resulting compositions are useful per se, as, for example, antibiotics, reagents for use in scientific research, and otherwise. Certain preferred compositions, comprising mixtures of such compounds, have been shown to have antibiotic activity and otherwise to be useful.
This invention is also directed to constituent portions of novel compounds, which components can be combined to form compositions having utility per se as well as in the preparation and identification of more complex pharmaceutical and other compositions.
In accordance with preferred embodiments of the present invention, compositions are provided comprising the reaction products of di-nitrogen heterocycles with chemically diverse substituents. Compounds of one such type have Formula I: 
wherein
each of n, x and y is 1, 2 or 3;
R1 is halogen, cyano, C1-C6 alkyl, perhalo C1-C3 alkyl, nitro, nitroso or carboxylate, and
R2 is hydrogen, C1-C6 alkyl, C6-C15 aryl, C7-C20 alkaryl, C4-C15 heterocycle or a moiety of the formula xe2x80x94(CH2)mxe2x80x94R3xe2x80x94R4 where
m is 0 or 1;
R3 is xe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(xe2x95x90S)xe2x80x94; and
R4 is xe2x80x94Oxe2x80x94R5, xe2x80x94N(R5)(R6), xe2x80x94N(R5)xe2x80x94Oxe2x80x94R6, C1-C6 alkyl, C6-C15 aryl or
C4-C15 heterocycle where R5 and R6 are independently hydrogen, C1-C6 alkyl, C6-C15 aryl, C3-C12 cycloalkyl, C4-C15 heterocycle or C7-C20 alkaryl.
It is preferred that such compositions comprise a plurality of compounds having Formula I (or other formulas set forth herein). Such compositions have been shown to have antibiotic activity and, hence, to be useful in the formulation of pharmaceuticals and otherwise.
In a preferred embodiment of the present invention, the compounds in accordance with Formula I are such that n is 1 or 2, and each of x and y is 2 or 3. More preferably n is 1, and x and y are 2.
In another preferred embodiment of the invention, R1 is halogen, cyano, C1-C6 alkyl, perhalo C1-C3 alkyl, nitro, or carboxylate. Exemplary C1-C6 alkyls include, methyl, ethyl, propyl, butyl, 1-butyl, pentyl and hexyl. Exemplary perhalo C1-C3 alkyls include, trifluoromethyl, trichloromethyl, truiodomethyl, pentafluoroethyl, pentachloroethyl, and heptafluoropropyl. Exemplary carboxylates include methyl carboxylate, ethyl carboxylate, t-butyl carboxylate, and sodium carboxylate. More preferably, R1 is fluorine, cyano, methyl, trifluoromethyl or methyl carboxylate.
In yet another preferred embodiment of the invention, R2 is hydrogen, C6-C15 aryl, C7-C20 alkaryl, C4-C15 heterocycle or a moiety of the formula xe2x80x94(CH2)mxe2x80x94R3xe2x80x94R4. Heterocycles are ring systems which contain one or more of heteroatoms, such as O, N or S, A heterocycle may be aromatic or contain one or more non-aromatic unsaturated bonds, i.e., xcfx80E-bonds. Exemplary C4-C15 heterocycles include pyran, pyrrolidone, benzothiazole, pyridine, benzoxazole, piperidine, piperazine, furan, thiofuran, pyrimidine and carbazole. Exemplary C6-C15 aryls include phenyl, aminophenyl, halophenyl, methoxyphenyl, hydroxyphenyl, toluyl, trifluoromethylphenyl, xylyl, ethylphenyl, propylphenyl, naphthyl, bromonaphthyl, chloronaphthyl, methylnaphthyl, hydroxynaphtyl, anthracyl, bromoanthracyl, and chloroanthracyl. Halophenyls are phenyl groups with one or more halogens substituted on the phenyl ring. Exemplary halophenyls include chlorophenyl, bromophenyl, chlorophenyl, fluorophenyl, dichlorophenyl, chlorofluorophenyl and dibromophenyl. A preferred halophenyl is o-chlorophenyl. Exemplary C7-C20 alkaryl include benzyl, methoxybenzyl, bromobenzyl, fluorobenzyl, naphthylmethyl, methoxyphenylmethyl, acetoxyphenylmethyl, 2-phenylethyl, 2-naphthylethyl, 3-phenylpropyl and 2-phenylpropyl.
More preferably, R2 is hydrogen, phenyl, halophenyl, -trifluoromethylphenyl, benzyl, m-methylbenzyl, m-nitrobenzyl, m-fluorobenzyl, -cyanobenzyl, m-trifluoromethylbenzyl, m-methylcarboxylbenzyl, 6-trifluoromethyl-2-pyridyl or a moiety of the formula xe2x80x94(CH2)mxe2x80x94R3xe2x80x94R4.
R3 is xe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(xe2x95x90S)xe2x80x94. Preferably, R3 is xe2x80x94CH2xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94, and m is 0 or 1.
R4 is xe2x80x94Oxe2x80x94R5, xe2x80x94N(R5)(R6), xe2x80x94N(R5)xe2x80x94Oxe2x80x94R6, C1-C6 alkyl, C6-C15 aryl or C4-C15 heterocycle. Preferably, R4 is xe2x80x94Oxe2x80x94R5, xe2x80x94N(R5)(R6), xe2x80x94N(R5)xe2x80x94Oxe2x80x94R6, C6-C15 aryl or C4-C15 heterocycle. Preferred C6-C15 aryl groups for R4 are phenyl, m-methylphenyl, -nitrophenyl, m-fluorophenyl, m-cyanophenyl, m-trifluoromethylphenyl or m-methylcarboxylphenyl. A preferred C4-C15 heterocycle for R is 3-(2xe2x80x2,4xe2x80x2-dichlorophenyl)-5-isoxazolyl.
R5 and R6 are independently hydrogen, C1-C6 alkyl, C6-C15 aryl, C3-C12 cycloalkyl, C4-C15 heterocycle or C7-C20 alkaryl. Preferably, R5 is hydrogen, C1-C6 alkyl or C7-C20 alkaryl. Preferred C1-C6 alkyl groups for R5 are methyl and t-butyl. Preferred C7-C20 alkaryl groups for R6 are benzyl, m-methylbenzyl, m-nitrobenzyl, m-fluorobenzyl, -cyanobenzyl, m-trifluoromethylbenzyl and m-methylcarboxylbenzyl.
Preferably R6 is hydrogen, C1-C6 alkyl, C3-C12 cycloalkyl, C4-C15 heterocycle or C7-C20 alkaryl. Cycloalkyl groups can be monocyclic, bicyclic, bridged cyclic or polycyclic. Cycloalkyl groups also can be substituted. Exemplary cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, adamantane, norcamphor, [3,3,0]bicyclooctane and norbomeol. A preferred C3-C12 cycloalkyl for R6 is cycloheptyl. A preferred C1-C6 alkyl for R6 is methyl. A preferred C4-C15 heterocycle for R6 is 2-benzothiazolyl, and a preferred C7-C20 alkaryl for R6 is benzyl.
In accordance with other embodiments of the present invention, compositions are provided comprising compounds having Formula II or III: 
wherein
p and s are independently 0, 1 or 2;
x and y are independently 1, 2 or 3;
Q1 and Q2 are independently xe2x80x94N(R15)xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
R2 is hydrogen, C1-C6 alkyl, C6-C15 aryl, C7-C20 alkaryl, C4-C15 heterocycle or a moiety of the formula xe2x80x94(CH2)mxe2x80x94R3xe2x80x94R4, where:
m is 0 or 1;
R3 is xe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(xe2x95x90S)xe2x80x94; and
R4 is xe2x80x94Oxe2x80x94R5, C1-C6 alkyl, C6-C15 aryl or C4-C15 heterocycle, where R5 is hydrogen, C1-C6 alkyl, C6-C15 aryl, C3-C12 cycloalkyl, C4-C15 heterocycle or C7-C20 alkaryl;
R11 and R14 are independently hydrogen, C1-C6 alkyl, C7-C20 alkaryl, C1-C20 aryl, C4-C15 heterocycle or C3-C20 cycloalkyl;
R12 and R13 are independently xe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94; and
each R15 is independently hydrogen or C1-C6 alkyl.
These compounds may be seen to relate to N-(aminoalkyl)- and/or N-(amidoalkyl)-di-nitrogen heterocycles. In certain preferred embodiments of the present invention, p and s are independently 0 or 1, and x and y are independently 2 or 3. More preferably, p and s are 1, and x and y are 2. In another preferred embodiment of the present invention, Q1 and Q2 are xe2x80x94N(R15)xe2x80x94.
It is also preferred in some embodiments of the present invention that R1, and R14 be independently C1-C6 alkyl, C7-C20 alkaryl, C6-C2 aryl, C4-C15 heterocycle or C3-C20 cycloalkyl. More preferably, R11 and R14 are independently C7-C20 alkaryl, C6-C20 aryl, C4-C15 heterocycle or C3-C20 cycloalkyl. Still more preferably, R11 and R14 are independently C6-C20 aryl, C4-C15 heterocycle or C3-C20 cycloalkyl. Even more preferably, R11 and R14 are independently selected from the group consisting of substituted or unsubstituted phenyl, furanyl, pyridyl, benzothiazolyl, thiofuranyl, naphthyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and cyclododecyl. Still even more preferably, R11 and R14 are independently 2-benzothiazolyl, cycloheptyl or p-methoxyphenyl.
In other preferred embodiments, R12 and R13 are independently xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94CH2xe2x80x94. In still other preferred embodiments, R15 is hydrogen, such that Q1 and Q2 are xe2x80x94NHxe2x80x94
Compounds which form the composition of the invention can be synthesized in accordance with reaction schemes employing standard, individual reactions. Exemplary reaction schemes are described in detail in the accompanying examples. However, persons of ordinary skill in the art should have no difficulty in determining routes to the synthesis of particular individual species or mixtures contemplated hereby.
In accordance with preferred embodiments of this invention, compositions are provided which comprise mixtures of compounds of the invention. Surprisingly, it has been found that such compositions have antibacterial activity, in some cases against both Gram negative and Gram positive bacteria.
Compositions comprising compounds disclosed herein are useful as antibiotics as well as in other therapeutic areas including treatment of fungal infections, viral infections, various type of neoplastic disease, cardiovascular diseases, central nervous system disorders, inflammation and immune disorders. Compositions of the present invention can inhibit both Gram positive bacteria, exemplified by Escherichia Coli (E. Coli), and Gram negative bacteria, such as Streptococcus Pyogenes (S. Pyogenes). Accordingly, the present invention provides therapeutic regimes against bacterial infection employing compositions set forth herein. In addition to antibiotic activities, compounds of the present invention are useful in other pharmaceutical areas and as intermediates for preparation and discovery of pharmaceutically active agents. The nitrogen heterocycles of the invention are likely to be useful in a number of therapeutic arenas, including muscle relaxants (as, for example, pipercurium bromide), anthelminthic drugs (as, for example, piperazine and its analogues), antineoplastic agents (as, for example, piposulfan), biological buffers (as, for example, piperazine derivatives such as piperazinediethanesulfonic acid), anti-ulcerative agents (as, for example, pirenzepine), antihypertensive agents (as, for example, prazosin), and anti-inflammatory agents (as, for example, protacine (proglumetacin)). Compounds of the present invention can also be used in or as an intermediate for preparing or discovering drugs useful in the treatment of neoplastic diseases, immune disorders, cardiovascular diseases, central nervous system disorders and inflammation, among others.
For pharmaceutical use, it is well within the skill of those skilled in the art to ascertain routes of drug administration and dosage levels for particular compositions of matter of this invention in view of the objects thereby to be attained. Thus, the dosage forms of the present invention can be administered orally, rectally, parenterally, or transdermally, alone or in combination with other psychostimulants, antidepressants, and the like to a patient in need of treatment. Oral dosage forms include tablets, capsules, dragees, and other conventional, pharmaceutical forms. Isotonic saline solutions, conveniently containing about 1-200 milligrams of drug per milliliter can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes. Rectal administration can conveniently be effected through the use of suppositories such as can easily be formulated from conventional carriers such as cocoa butter. Transdermal administration can be effected through the use of transdermal patch delivery systems and the like. The preferred routes of administration are oral and parenteral.
The dosage employed should be carefully titrated to the patient, considering age, weight, severity of the condition, and clinical-profile. The actual decision as to dosage will depend upon the exact drug being employed and will be made by the attending physician as a matter of routine. Such physician can, however, determine an appropriate regime employing well-known medical considerations. Unit dosage forms are selected as a matter of routine depending upon the selected route of administration. For oral administration, formulation into tablets using tabletting excipients are conveniently employed, although capsular and other oral forms are also useful.
The terms xe2x80x9cpharmaceuticalxe2x80x9d, xe2x80x9cpharmaceutically activexe2x80x9d and xe2x80x9cpharmaceutically usefulxe2x80x9d are used interchangeably herein and refer to ability of the compounds of the present invention to provide some therapeutic or physiological beneficial, effect. As used herein, the terms include any physiologically or pharmacologically activity that produces a localized or systemic effect or effects in animals, including warm blooded mammals such as humans. Pharmaceutically active agents may act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autocoid systems, the alimentary and excretory systems, the histamine system and central nervous systems as well as other biological systems. Thus, the compounds of the present invention may be used as sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, antiinflammatories, local anesthetics, muscle contractants, antibiotic, antiviral, antiretroviral, antimalarials, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplastics, antineoplastics and chemotherapy agents. The compounds of the present invention could further be used to treat cardiovascular diseases, central nervous system diseases, cancer, metabolic disorders, infections and dermatological diseases as well as other biological disorders and infections.
Among the uses of the compositions and compounds of the present invention are uses in scientific research as research reagents. In accordance with the present invention, it is now possible to prepare pluralities of compounds in accordance with the invention to form a composition of matter in the nature of a xe2x80x9clibraryxe2x80x9d of compounds for research. Such libraries are known to be useful, per se and are important in the discovery, inter alia, of new drugs. In view of the chemical diversity present in such compounds, e.g. the large number of functional groups and functionalizable sites, a very large number of different compounds can be prepared. Moreover, such compounds can be prepared differentially, that is, in such a fashion that a population of known species can be prepared reliably, ensuring that all potential members of a family of chemical species are, in fact, synthesized.
In view of the foregoing, persons of ordinary skill in the art will know how to synthesize such libraries, comprising chemical compositions within the scope and spirit of this invention, and to assay the libraries against etiological agents or in tests or assays, in order to identify compounds having antibacterial, antifungal, antiviral, antineoplastic or other desired pharmaceutical, biological, or chemical activity.
For example, compounds of the present invention may be used in any of the many combinatorial drug identification methodologies known to persons skilled in the art of subsequently developed. Exemplary uses of this type are those described in Fodor et al., U.S. Pat. No. 5,489,678; Pirrung et al. U.S. Pat. No. 5,143,854; Lerner et al., PCT patent application WO 93/20242; Lebl et al. PCT patent application WO 94/28028; Hollis et al. PCT patent application WO 93/22678; Brennan U.S. Pat. No. 5,472,672, Nishioka U.S. Pat. No. 5,449,754 and Ecker et al., PCT patent application WO 93/04204.
As will be readily apparent to persons of skill in the art from a review of the present specification, useful compositions can be obtained by preparing mixtures of compounds formed from the constituent moieties forming the present compounds. Thus, compounds formed by reacting reactive appendage compounds such as meta benzylic compounds, alpha-amide compounds or other compounds having a reactive group thereupon, with one or a family of scaffold molecules having a plurality of reactive functionalities thereupon have great utility as pharmaceuticals. It is preferred that the scaffold molecules have at least one reactive functionality which can react with the reactive functionality on the appendage molecules, together with at least one additional reactive moiety for reaction with other appendages or functional groups. For example, the scaffold molecules conveniently have nucleophilic functionalities while the appendage molecules are comprise one or more leaving groups. The reverse can also be true, however, such that the scaffold molecules have electrophilic centers and leaving groups while the appendages are nucleophilic. Other reactions may also be employed in this context in addition to nucleophilic substitution reactions.
For meta benzyl compounds, it is preferred that the reactive functions reside on the benzylic carbon atom and that the same comprise a leaving group. For the alpha-amides, which are also preferred, the reactive functional group is also a leaving group, but may conveniently reside alpha to the carbonyl. Preferably, the leaving group is a halogen, such that the groups are alpha haloamides. Other appendage molecules and a wide variety of functional groups thereupon may be employed in accordance with the spirit of this invention.
Preferred scaffold molecules are those which possess at least two functional groups, at least one of which can react with appendage molecules. It is preferred that two or more functional groups be present such that great diversity of resulting species can be attained. Thus, scaffolds having two, three and more functional groups reactive with appendage moleculesxe2x80x94either in the same chemical way or in different waysxe2x80x94are highly useful in the practice of this invention. Preferred scaffold species are di-nitrogen heterocycles as disclosed herein. Many other scaffold species can be used, however.
It is preferred to react a plurality of appendage molecules with the scaffold molecules and also, in some preferred cases, to provide a plurality of scaffold molecules for such reactions. The resulting compositions can be seen to be mixtures of reaction species. One preferred use for such mixtures is in the identification of chemical species which have biological activity, especially pharmaceutical activity. Such mixtures can be screened for activity and active molecular species determined. Such mixtures, conventionally denominated xe2x80x9clibrariesxe2x80x9d are useful per se, and are well known to be useful in the chemical and pharmaceutical industry, where the preparation and exchange of libraries for screening is a common undertaking.
It will be appreciated that the present invention provides highly diverse libraries for this purpose in addition to the antibacterial activity shown by many such libraries.
It will also be appreciated that compounds contemplated by the present invention include modification of the species set forth herein. Thus, conjugates, oligomers, and other related species having the chemical properties called for are within the spirit of this invention.